Identification of the Autophosphorylation Sites of LRRK2

Kamikawaji, Shogo; Ito, Genta; Iwatsubo, Takeshi

doi:10.1021/bi9011379

Cited by 99 publications

(102 citation statements)

References 24 publications

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“…LRRK2 has been found to autophosphorylate > 20 serine and threonine residues in vitro 37, 50, 56, 57, 58, 59, 60, 61. The majority of the autophosphorylation sites reside in the ROC domain, with only a few in the COR and kinase domains (Fig.…”

Section: Importance Of Lrrk2 Autophosphorylation and Constitutive Phomentioning

confidence: 99%

Cellular processes associated with LRRK2 function and dysfunction

Wallings¹,

2015

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Mutations in the leucine‐rich repeat kinase 2 (LRRK2)‐encoding gene are the most common cause of monogenic Parkinson's disease. The identification of LRRK2 polymorphisms associated with increased risk for sporadic Parkinson's disease, as well as the observation that LRRK2‐Parkinson's disease has a pathological phenotype that is almost indistinguishable from the sporadic form of disease, suggested LRRK2 as the culprit to provide understanding for both familial and sporadic Parkinson's disease cases. LRRK2 is a large protein with both GTPase and kinase functions. Mutations segregating with Parkinson's disease reside within the enzymatic core of LRRK2, suggesting that modification of its activity impacts greatly on disease onset and progression. Although progress has been made since its discovery in 2004, there is still much to be understood regarding LRRK2′s physiological and neurotoxic properties. Unsurprisingly, given the presence of multiple enzymatic domains, LRRK2 has been associated with a diverse set of cellular functions and signalling pathways including mitochondrial function, vesicle trafficking together with endocytosis, retromer complex modulation and autophagy. This review discusses the state of current knowledge on the role of LRRK2 in health and disease with discussion of potential substrates of phosphorylation and functional partners with particular emphasis on signalling mechanisms. In addition, the use of immune cells in LRRK2 research and the role of oxidative stress as a regulator of LRRK2 activity and cellular function are also discussed.

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Section: Importance Of Lrrk2 Autophosphorylation and Constitutive Phomentioning

confidence: 99%

Cellular processes associated with LRRK2 function and dysfunction

Wallings¹,

2015

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“…An analysis of autophosphorylated LRRK2 by matrix assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometery revealed that Ser1403, Thr1404, Thr1410, Thr1491 in the ROC domain, as well as Thr1967 and Thr1969 in the kinase domain, can all be autophosphorylated (60). Kinase assays of LRRK2 using various synthetic peptides showed that the enzyme prefers to phosphorylate Thr over Ser residues, and one study developed a synthetic peptide, Nictide, as a LRRK2 substrate for in vitro kinase assays (61).…”

Section: Molecular Biological Features Of Lrrk2 and Its Pathological mentioning

confidence: 99%

Biochemical and molecular features of LRRK2 and its pathophysiological roles in Parkinson's disease

Seol

2010

BMB Reports

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Parkinson's disease (PD) is the second most common neurodegenerative disease, and 5-10% of the PD cases are genetically inherited as familial PD (FPD). LRRK2 (leucine-rich repeat kinase 2) was first reported in 2004 as a gene corresponding to PARK8, an autosomal gene whose dominant mutations cause familial PD. LRRK2 contains both active kinase and GTPase domains as well as protein-protein interaction motifs such as LRR (leucine-rich repeat) and WD40. Most pathogenic LRRK2 mutations are located in either the GTPase or kinase domain, implying important roles for the enzymatic activities in PD pathogenic mechanisms. In comparison to other PD causative genes such as parkin and PINK1, LRRK2 exhibits two important features. One is that LRRK2's mutations (especially the G2019S mutation) were observed in sporadic as well as familial PD patients. Another is that, among the various PDcausing genes, pathological characteristics observed in patients carrying LRRK2 mutations are the most similar to patients with sporadic PD. Because of these two observations, LRRK2 has been intensively investigated for its pathogenic mechanism (s) and as a target gene for PD therapeutics. In this review, the general biochemical and molecular features of LRRK2, the recent results of LRRK2 studies and LRRK2's therapeutic potential as a PD target gene will be discussed. [BMB reports 2010; 43(4): 233-244]

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“…Reciprocal regulation of GTP binding by the kinase domain may also occur, as LRRK2 autophosphorylates several residues within the ROC domain. Phosphorylation of T1491 and T1503 residues apparently diminishes GTP binding [24][25][26][27][28][29], suggesting that LRRK2 GTPase may be functionally downstream of the kinase activity [30], although more complex situations may occur. These suggestions show that there is intramolecular communication between different LRRK2 domains, pointing out how complex the molecule is.…”

Section: Introductionmentioning

confidence: 99%

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Rudenko

Cookson

2014

Neurotherapeutics

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Variation within and around the leucine-rich repeat kinase 2 (LRRK2) gene is associated with familial and sporadic Parkinson's disease (PD). Here, we discuss the prevalence of LRRK2 substitutions in different populations and their association with PD, as well as molecular and cellular mechanisms of pathologically relevant LRRK2 mutations. Kinase activation was proposed as a universal molecular mechanism for all pathogenic LRRK2 mutations, but later reports revealed heterogeneity in the effect of mutations on different activities of LRRK2. One mutation (G2019S) increases kinase activity, whereas mutations in the Ras of complex proteins (ROC)-C-terminus of ROC (COR) bidomain impair the GTPase function of LRRK2. Some risk factor variants, including G2385R in the WD40 domain, actually decrease the kinase activity of LRRK2. We suggest a model where LRRK2 mutations exert different molecular mechanisms but interfere with normal cellular function of LRRK2 at different levels of the same downstream pathway. Finally, we discuss the current state of therapeutic approaches for LRRK2-related PD.

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Identification of the Autophosphorylation Sites of LRRK2

Cited by 99 publications

References 24 publications

Cellular processes associated with LRRK2 function and dysfunction

Cellular processes associated with LRRK2 function and dysfunction

Biochemical and molecular features of LRRK2 and its pathophysiological roles in Parkinson's disease

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

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